Respiratory System

To this group are concerned drugs that are used for the treatment of (1) bronchial constriction, (2) cough, (3) depression of respiratory, (4) pulmonary edema, (5) for the bettering of sputum expelling.

Bronchodilators and other agents used in bronchial asthma.

Bronchial asthma is physiologically characterized by widespread narrowing of the airways. It is a disease mediated by reaginic (IgE) antibodies bound to mast cells in the airway mucosa. Bronchial spasm appears in result of disorders in neural and humoral regulation of bronchial muscle’s tonus. To neural factors are considered depression of β2-adrenoreceptors and activation of M-cholinoreceptors. Humoral factors, that provoke bronchial spasm, are mediators of allergic reactions (histamine, serotonin, substance of anaphylaxis, etc.), that are excreted by basophilic cells and thrombocytes. Its pathologic features are contraction of airway smooth muscle, mucosal thickening from edema and cellular infiltration, and inspissation in the airway lumen of abnormally thick, viscid plugs of mucus. Of these causes of airway obstruction, contraction of smooth muscle is most easily reversed by current therapy; reversal of the edema and cellular infiltration requires sustained treatment with anti-inflammatory agents. In case, when asthma has infective-allergic nature, anti-microbe drugs are also used.

Classification of bronchi widening (broncholytics) drugs:

1.	β-adrenomimetics

1.1 non-selective β1+β2-adrenomimetics (orciprenaline, isadrine) and α+β-adrenomimetics (adrenaline, ephedrine);

1.2 selective β2-adrenomimetics (salbutamol, fenoterol, terbutalin).

2. M-cholinolytics (ipratropium bromide, atropine, platyphylline);

3.	Myotrope drugs (euphylline, theophylline, no-spa);

4.	Anti-inflammatory, anti-allergic and desensitizative drugs (glucocorticoids, cromolyn-sodium, ketotifene, H1-histaminoblockers);

5.	Complex drugs (theophedrine, solutane, antasman).

The adrenoceptor agonists, have several pharmacologic actions that are important in the treatment of asthma i.e., they relax airway smooth muscle and inhibit release of some bronchoconstricting substances from mast cells. As in other tissues, the β-agonists stimulate adenylate cyclase and catalyze the formation of cAMP in the airway tissues. Although there is no evidence for direct sympathetic innervation of human airway smooth muscle, there is ample evidence for the presence of adrenoreceptors on airway smooth muscle. The adrenomimetic agents that have been widely used in the treatment of bronchial asthma include adrenaline, ephedrine, isadrine, and a number of 2-selective agents.

Adrenaline (epinephrine) is an effective, rapidly acting bronchodilator when injected subcutaneously. Because adrenaline stimulates  as well as α receptors, tachycardia, arrhythmias, worsening of angina pectoris, and hypertension are troublesome adverse effects. Compared with adrenaline, ephedrine has a longer duration (4-6 hours), oral activity, more pronounced central effects, and much lower potency. Ephedrine acts at indirect way – it stimulates the releasing of noradrenaline from presynaptic membrane. It is prescribed in fixed-dose combination with spasmolytics (theophylline), H1-histaminoblockers (dimedrole) in commercial formulations.

Isadrine (isoproterenol) is a potent bronchodilator; when inhaled as a microaerosol, it causes maximal bronchodilation within 5 minutes. Isadrine has a 60- to 90-minute duration of action. It stimulates both β1 and β2 receptors, that’s why it causes tachycardia, arrhythmias, and evokes the attack of angina pectoris. Because nonselective adrenomimetics cause more cardiac stimulation (mediated by 1 receptors), they are replaced by selective β2-adrenomimetics.

The βselective adrenoceptor agonist drugs are the most widely used adrenomimetics for the treatment of asthma at the present time. These agents are effective after inhaled or oral administration and have a long duration of action and significant 2 selectivity. Salbutamol (albuterol), terbutaline, and fenoterol are available as metered-dose inhalers. Bronchodilation is maximal by 30 minutes and persists for 3-4 hours. Salbutamol and terbutaline are also prepared in tablet form. One tablet two or three times daily is the usual regimen. Of these agents, only terbutaline is available for subcutaneous injection. The indications for this route are similar to those for subcutaneous adrenaline severe asthma requiring emergency treatment. The principal adverse effects of selective β2-adrenomimetics are skeletal muscle tremor, nervousness, and occasional weakness.

Interest in the potential value of M-cholinolytics has recently been increased by demonstration of the importance of the vagus in bronchospastic responses of laboratory animals and by the development of a potent agent that is poorly absorbed after aerosol administration to the airways and is therefore not associated with systemic atropine effects.

M-cholinolytics competitively inhibit the effect of acetylcholine at muscarinic receptors. In the airways, acetylcholine is released from efferent endings of the vagus nerves, and M-cholinolytics can effectively block the contraction of airway smooth muscle and the increase in secretion of mucus that occurs in response to vagal activity. Very high concentrations are required to inhibit the response of airway smooth muscle to nonmuscarinic stimulation. This selectivity of muscarinic antagonists limits their usefulness in preventing bronchospasm.

M-cholinolytics are effective bronchodilators. When given intravenously, atropine, the prototypical M-cholinolytic, causes bronchodilation at a lower dose than that needed to cause an increase in heart rate. Deposition of the aerosol in the mouth frequently causes a local drying effect. Adverse effects due to systemic absorption include urinary retention, tachycardia, loss of visual accommodation, and agitation.

Systemic adverse effects limit the quantity of atropine sulfate that can be given, but the development of a more selective quaternary ammonium derivative of atropine, ipratropium bromide (atrovent), permits delivery of high doses to muscarinic receptors in the airways because the compound is poorly absorbed and does not readily enter the central nervous system. Its effect appears after 20-30 minutes, reaches maximum within 1,5-2 hours and lasts 4-8 hours.

Theophylline as well as caffeine are the derivatives of methylxanthines. At high concentrations, it inhibits the enzyme phosphodiesterase, which hydrolyzes cyclic nucleotides. This inhibition results in higher concentrations of intracellular cAMP. This effect could explain the cardiac stimulation and smooth muscle relaxation produced by these drugs, but it is not certain that sufficiently high concentrations are achieved in vivo to inhibit phosphodiesterase. Another proposed mechanism is the inhibition of cell surface receptors for adenosine that has been shown to cause contraction of isolated airway smooth muscle and to enhance histamine release from cells present in the lung. These effects are antagonized by theophylline, which blocks cell surface adenosine receptors. Besides broncholytic effect, theophylline dilates vessels of the lung, kidneys, heart, skeleton muscles, lowers hemodynamic loading on heart. It causes direct cardiotonic action and increases oxygen needs.

A lot of complex drugs include theophylline. Euphylline (theophylline + ethylendiamine), xantinole nicotinate (theophylline + nicotinic acid), etc are the most known. Euphylline is well absorbed (90%) after enteral introducing. For removing of bronchial asthma attack it is introduced intravenously or intramuscularly, however it causes irritate action. Therapeutic effect lasts 6 hours. Metabolism is done in liver; it is slower during the depression of hepatic enzymes, evoked by drugs (e.g., H2-histaminoblockers). In such cases smaller doses of euphylline are needed. It is excreted by kidneys in form of metabolites (90%) and in non-transformed form (10 %). Adverse effects include excitation of the CNS (anxiety, insomnia, tremor, cramps), tachycardia, arrhythmia, sometimes-cardiac insufficiency. Xantinole nicotinate is used for the treatment of diseases that accompanied by vessel contraction (e.g., atherosclerosis).

Another spasmolytics are papaverine, no-spa. They have a direct relaxant effect on vascular, bronchial and other smooth muscle due to inhibition of the enzyme phosphodiesterase and accumulation of cAMP in the smooth muscles. These agents are indicated for the treatment of spasm of the gastrointestinal tract, bronchi, etc. As the rule, papaverine and no-spa are used in combination with another broncholytics. Anti-allergic, desensitizative and anti-inflammatory drugs include cromolyn sodium, ketotifen, corticosteroids.

Cromolyn sodium differ from most antiasthmatic medications in that it is only of value when taken prophylactically. Cromolyn inhibits mast cell release of histamine, leukotrienes, and other substances that cause hypersensitivity reactions. When used as aerosol (metered-dose inhalers), it effectively inhibit both antigen- and exercise-induced asthma, and chronic use (four times daily) may reduce the overall level of bronchial reactivity; however, this drug has no effect on airway smooth muscle tone and is ineffective in reversing asthmatic bronchospasm. Cromolyn is poorly absorbed from the gastrointestinal tract. For use in bronchial asthma, it must be applied topically by inhalation. When given by inhalation or orally, less than 10% is absorbed, and most is excreted unchanged.

Ketotifen has antihistamine and antiallergic activities. It inhibits mast cell release of histamine, leukotrienes, and other substances that cause hypersensitivity. In addition, ketotifen blocks H1-receptors. Agent is well absorbed from gastrointestinal tract. The serum half-life is about 20 hours. Ketotifen is used for the prevention of acute bronchospasm. Adverse effects include drowsiness and thrombocytopenia. Like cromolyn, corticosteroids do not relax airway smooth muscle directly but reduce bronchial reactivity, increase airway caliber, and reduce the frequency of asthma exacerbations if administered for some time. Their effect on airway obstruction may be due in part to their potentiation of the effects of β-receptor agonists, but their most important action is their inhibition of the eosinophilic airway mucosal inflammation in asthmatic airways. The principal anti-inflammatory action is the inhibition of the release of arachidonic acid from cell membranes and therefore reduction of the production of leukotrienes, prostaglandins, and cytokines. Aerosol treatment is the most effective way to decrease the systemic adverse effects of corticosteroid therapy. Inhalation of lipid-soluble corticosteroid such as beclometasone makes it possible to deliver corticosteroids to the airways with minimal systemic absorption. Effect develops gradually, so it is not used for turning out of attack. Because of severe adverse effects when given chronically, oral and parenteral corticosteroids (prednisolone, beclometasone, triamcinolone) are generally reserved for patients who require more urgent treatment, i.e., those who have not improved adequately with bronchodilators or who experience worsening symptoms despite maintenance therapy.

Adverse effects during short courses (less than 7 days) usually are absent, during prolonged using – hyperglycemia, hypertension, osteoporosis, adrenal cortex insufficiency, etc may appear. A special problem caused by inhaled topical corticosteroids is the occurrence of oropharyngeal candidiasis.

Combined drugs (theophedrine, solutane, antasman, etc.) are used for turning out and prophylaxis of bronchial asthma attacks. Principe of combining is based on synergetic interaction of the drugs with different mechanism of action. For example, solutan (alkaloids of belladonna + ephedrine + sodium iodide, etc), aerosol of berodual (fenoterol + ipratropium bromide), tablets of theophedrine (theophylline + ephedrine + extract of belladonna), etc.

Antitussive and expectorant drugs.

Self-cleaning of mucosa of the respiratory ways from strange bodies is done by fastening of bronchial glands secretion, increasing of epithelium’s activity and bronchioles motility. Irritation of reflective zones, especially in region of trachea’s bifurcation, is accompanied by cough. Couch is a protective reaction, which promotes deleting of irritate agent from breathing ways. But during inflammation of the mucosa, secret becomes glutinous due to cumulated proteins, leukocytes and is hardly excreted. Drugs that depress cough (anti-cough, antitussive) and drugs that better excretion of sputum (expectorants) are used for weakening of cough.

Antitussive drugs are divided into 2 groups: (1) drugs of central action (codeine, ethylmorphine, glaucin); (2) drugs of peripheral action (libexine).

Codeine and ethylmorphine are the phenanthrene-derivative opiate agonists that have antitussive properties. They cause suppression of the cough reflex by a direct effect on the cough centre in the medulla of the brain. Also these agents have mild analgesic and sedative effects. Codeine and ethylmorphine are well absorbed from the GI tract. Following oral administration, peak antitussive effects usually occur within 1-2 hours and antitussive activity may persist for 4 hours. High doses of codeine and ethylmorphine can cause depression of breathing centre, lowering of lung ventilation, and constipation. Prolonged therapy may results in addiction (dependence). Glaucin is an alkaloid of glaucium flavum. It depresses cough centre. But it doesn’t inhibit breathing, doesn’t cause drug addiction and constipation. It possesses adrenolytic effect and may lower AP, so it is not recommended during hypotonia.

Libexine apparently inhibits cough production by anesthetizing stretch receptors of vagal afferent fibers in the bronchi, pharyngis, and trachea that mediate the cough reflex.

Antitussives are used in the symptomatic relief of nonproductive cough during bronchitis, bronchial asthma, pneumonia, etc. Since the cough reflex may be a useful physiologic mechanism, which clears the respiratory passages of foreign material and excess secretions and may aid, in preventing or reversing atelectasis, cough suppressants should not be used indiscriminately.

According to the mechanism of action expectorants are divided into: (1) drugs that stimulate the sputum expectoration (secretomotoric drugs) and (2) mucolytic agents. Expectorants have been used in the symptomatic management of conditions such as chronic bronchitis, bronchiectasis, and bronchial asthma that are associated with high sputum viscosity and hard expulsion of sputum.

Secretomotoric drugs are subdivided into agents of reflective action and agents of resorptive action. It is postulated that expectorants of reflective action irritate the stomach mucosa. Because stomach mucosa as well as bronchi is innervated by nervus vagus, the irritation of stomach activates the centre of nervus vagus in medulla that results in hastening of bronchial gland secretion, stimulation of bronchial epithelium and bronchioles peristaltic. It is accompanied by diluting of sputum and mucus and their expelling by cough. Due to irritative properties, reflective expectorants in high doses may cause vomiting. Drugs of reflective action are administered primarily in form of infusions, decocts, tinctures, extracts, mixtures, some (e.g., thermopsis) in form of tablets. For examples, infusion of thermopsis grass, althea roots, tablets mucaltin (contains the extract of althea root), etc.

To drugs of resorptive action are concerned substances with iodine, ammonium chloride, sodium bicarbonate, etc. After absorption those drugs are excreted by bronchial glands, stimulating secretion and motor function of epithelium and bronchioles. Finally, they decrease the viscosity of mucus and promote it expelling. Prolong iodine therapy may cause symptoms of iodism: rhinitis, salivation, lacrimation, rash. Hypersensitivity reactions to iodides may occur and may be manifested by angioedema, fever, arthralgia, and eosinophilia.

Mucolytics act directly on glutinous secret. They reduce the viscosity of purulent and nonpurulent pulmonary secretions and facilitate their removal by coughing or postural drainage. Mucolytics are proteolytic enzymes (trypsin, chymotrypsin, deoxyribonuclease), acetylcysteine, bromhexine, etc. Trypsin hydrolyzes peptides, amides. Deoxyribonuclease hydrolyzes phosphodiester bonds in DNA and proteins. Bromhexine depolymerases and hydrolyzes fibers of mucopolysaccharides. Also bromhexine promotes the synthesis of surfactant (a surface-active agent that stabilize alveolar volume). Acetylcysteine reduces disulfide linkages of mucoproteins. Predominantly mucolytics are administrated in inhalation route, except bromhexine that is used orally. Mucolytics are used in the adjunctive treatment of patients with abnormal, viscid, or thick mucous secretions in such conditions as pneumonia, bronchitis, emphysema, tracheobronchitis, bronchiectasis, etc. In general mucolytics are combined with anti-microbe drugs, broncholytics.

Stimulators of the breathing (analeptics)

Stimulators of respiratory and cardio-vascular centres of medulla are used during depression of these centres. Because they restore life-important functions (breathing and blood circulation) they are called analeptics (animate substances). Most analeptics in higher doses may cause cramps. Analeptics are the antagonists of narcosis and soporific substances, alcohol, narcotic analgesics and cause “awakening” effect, which is characterized by smaller deepness and durability of narcosis and sleep, restoring of reflexes, muscular tonus and consciousness. Mechanism of analeptic's action is related with increased excitability of neurons.

Analeptics are divided into 3 groups:

1.	Agents of direct action on breathing centre (bemegrid, ethimisole, strychnine, caffeine);

2.	Agents of reflective action (lobelin, cytiton)

3.	Agents with combined action (cordiamine, camphor, CO2);

Bemegrid is used basically during poisoning by barbiturates and narcosis substances, for quick turning out from narcosis. It is injected slowly intravenously by 5-10 ml of 0,5 % solution every 3-5 minutes up to restoring of breathing, blood circulation and reflexes. Injecting has to be stopped on the first appearance of cramp contraction of muscles.

Ethimisole engages especial place, because together with excitation of medulla centres it causes depressive action on the cortex. It is used basically during poisoning by narcotic analgesics, and also in psychiatric practice as sedative drug. Ethimisole stimulates the production of adrenocorticotrope hormone of pituitary that increases the serum corticosteroids level and results in anti-inflammatory and anti-histamine effects. That’s why ethimisole is used for the treatment of bronchial asthma and arthritis.

Caffeine is described in chapter “Psychostimulators”. Analeptic effect appears during injection of high doses that simulate centres of medulla. It causes expressed cardiotonic action. Caffeine is administered for the treatment of alcohol poisoning and during combine respiratory and cardiac insufficiency.

Strychnine is an alkaloid from strychnos. It stimulates all parts of the central nervous system, and was used as an antidote for depressant poisons. It caused the bettering of vision, hearing, tactile sensitiveness, muscular tonus, and metabolism. So, strychnine causes general tone action and sometimes used for the treatment of chronic fatigue, hypotension, functional impairment of vision and hearing, etc. Strychnine blocks the inhibitory neurotransmitter, glycine, and thus can cause convulsions. It is a potent chemical capable of producing acute or chronic poisoning of humans or animals.

Cytiton and lobelin are the N-cholinomimetics. They stimulate respiratory centre in reflective way due to excitation of N-cholinoreceptors in the carotid sinus (carotid bulb). After intravenous injection of N-cholinomimetics one can see quick but short respiratory stimulation. They are used for the treatment of reflective respiratory depression during different traumas, inspiration of irritating substances and carbon monoxide. Cytiton raises the blood pressure, thus it is recommended for the shock, collapse. Analeptics of combined action both directly and indirectly (through the carotid sinus) stimulate respiratory centre. Cordiamine is a derivative of nicotinic acid. It stimulates breathing and blood circulation due to the stimulation of medulla centres. Also it directly stimulates heart activity. It is administered during weakening of breathing and blood circulation, caused by intoxication, infection disease, shock, etc.

Camphor is a ketone distilled from the tree of Cinnamonum camphora, and also prepared synthetically from oil of turpentine. Part of camphor is excreted through breathing ways that promotes expelling of the sputum. Locally agent causes irritate and antiseptic action. It directly stimulates centres of the medulla. Also camphor stimulates the contractility and metabolism of myocardium. Camphor increases blood pressure due to narrowing of the vessels in abdominal organs. In the same time it dilates vessels of the brain, lungs, and heart. It is used in form of oil solutions subcutaneously for the treatment of acute and chronic cardiac insufficiency, collapse, depression of the breathing centre, etc. Locally it is administered in form of ointments during inflammatory processes, itch, for prophylaxis of bedsores, etc.

Carbonic dioxide (CO2) is a potent respiratory stimulant. Inspiration of 3% CO2 increases the lung ventilation in 2 times. Carbonic dioxide can be used for inhalation separately or in combination with oxygen (carbogen). Carbonic dioxide activates the cardio-vascular centre. In the same time it dilates the smooth muscles due to the direct action. Carbonic dioxide is used for the stimulation of respiratory during poisons by narcosis substances, carbon monoxide (CO), during asphyxia of newborns. In higher doses CO2 can cause hypercapnia, acidosis, and paralysis of breathing centre.

Drugs, used during pulmonary edema

Edema of lungs is accompanied by acute respiratory insufficiency, so it needs emergency therapy. Pulmonary edema can be an aggravation of left-ventricular cardiac insufficiency, poisoning by irritate gases, during uremia, anaphylactic shock, infections, craniofacial traumas, coma, etc.

The most characteristically features of pulmonary edema are fear, cyanosis, bubbling respiratory with pink foamy sputum. The main danger of pulmonary edema is foaming of edema’s liquid in respiratory ways, which causes hypoxia. So, inhalation of anti-foaming drugs, oxygen and also sucking of the foam are necessary. Anti-foaming substances are ethyl spirit and anti-foamsilane. They diminish the foam’s surface tension and transform foam into liquid, which volume considerably smaller. They are administered in form of inhalations with oxygen. Anti-foamsilane doesn’t irritate breathing ways, doesn’t depress CNS and acts quicker than spirit. If pulmonary edema is associated with cardiac insufficiency, cardiac glycosides (strophantine, corglycon) are indicated. During edema that is associated with hypertension one can use ganglioblockers (hygronium, benzohecsonium), α-adrenolytics (phentolamine, aminazine), myotrope vessel narrowing drugs (sodium nitroprusside). Adrenomimetics (mesathon, ephedrine) are used in case of hypotension. In addition during pulmonary edema are indicated diuretics (furosemide) that cause dehydration of lung parenchyma, glucocorticoids (prednisolone) that possess anti-edema and anti-inflammatory action, narcotic analgesics (morphine) that lower venous input to heart and blood-filling of lungs, depress short breathing and coughing, cause sedative action.